See “EEG Abnormalities Are Associated With Increased Risk of Transplant or Poor Outcome in Children With Acute Liver Failure” by Wainwright et al on page 449.
The article by Wainwright et al (1) in this issue of the Journal of Pediatric Gastroenterology and Nutrition concludes that their work is an “initial step” in correlating neurologic findings with outcome in pediatric acute liver failure (PALF). Indeed it is, but emphasis must be placed on initial step.
A retrospective analysis of a “clinical pathway” initiated in 2008 to assess and manage neurologic findings in PALF is presented, with 19 children analyzed. Clinical hepatic encephalopathy (HE) score, electroencephalogram (EEG), and radiographic imaging of the brain with computerized axial tomography and/or nuclear magnetic resonance imaging were used to assess neurologic function. Assessments were performed early in the hospital course, but the duration or management of the illness before the intensive care unit admission is not known. Administration of L-carnitine and maintenance of patient temperature at <37.5°C, presumably by cooling, were included in the pathway, although neither has been rigorously studied in PALF. Outcomes were death (n = 4) or survival with either their native liver (S-NL; n = 10) or following liver transplantation (S-LT; n = 5) at the time of hospital discharge. There was no comment on neurologic outcome following hospital discharge.
Clinical tools to assess HE developed >30 years ago to support clinical trials in adults with cirrhosis and portal-systemic encephalopathy (PSE) included the PSE index (2) and West Haven criteria (WHC) (3). WHC were simpler and segregated into grades I to IV based on alterations of consciousness, intellectual function, and behavior. Although not developed to assess HE in acute liver failure (ALF), WHC were selected as the best tool to assess adults with ALF (4). Absent a pediatric specific tool to assess acute HE, WHC are generally used in older children. A pediatric modification of WHC was proposed by Whitington and Alonso for children <4 years old (5,6). In the Wainwright et al study (1), initial and highest recorded HE scores did not differ between S-NL and S-LT, but were higher in those who died. In the PALF study, 20% of children who never developed clinical HE during the first 7 days of study entry were either dead or had received an LT by 21 days, and 22% of those with a maximum coma score of IV were alive at 21 days (5). There is a need for better methods to assess HE in PALF, and Wainwright et al have moved us down that road.
Principles of EEG monitoring to predict outcome were derived from studies on traumatic brain injury and cardiac arrest, but PALF is not a single entity. Rather, PALF is a clinical syndrome caused by myriad diagnoses categorized within metabolic, infectious, toxic, immune-mediated, and indeterminate conditions. Only a few of these conditions were represented in this study. Different etiologies of PALF may have different EEG patterns, as suggested in an adult study of hospitalized patients with encephalopathy from different etiologies (7). Therefore, to identify EEG patterns that may segregate not only immediate and long-term survival and neurocognitive outcome but also diagnosis will require a much larger cohort of well-characterized children with PALF.
The present study suggests that incorporation of EEG monitoring in patients with PALF may enlighten assessment of neurologic dysfunction. Unblinded EEG findings were normal in 7 of 18 patients (5 S-NL, 2 S-LT), but were “profoundly abnormal” in all 3 patients who had an EEG before death. The interrater agreement for EEG interpretation was not reported, and definitions for mild, moderate, and severe slowing on EEG were missing, but slowing was the only EEG abnormality in 6 patients, 3 S-NL with mild slowing and 3 S-LT with moderate-to-severe slowing. Although this small, highly selected, and single-center cohort makes it impossible to generalize their findings to all patients with PALF, the authors provide important observational data to justify further study.
Neuroimaging did not reveal evidence of cerebral edema, but an intracranial pressure (ICP) monitor was placed in 3 patients (2 LT, 1 death) and found only 1 with elevated ICP in the mid-20s. A study of 26 adults with ALF and grade 3 or 4 HE defined elevated ICP as >25 mmHg, with median ICP pressures in the high ICP group that ranged from 38 to 84 mmHg (8). Therefore, the clinically important elevation of ICP in PALF has yet to be clarified. Cerebral blood flow was not reported. For analytical purposes, death and S-LT were combined into a single outcome, but evidence suggests that the S-LT cohort is a combination of patients who would have lived with their native liver and died had LT not been available (9,10).
Additional opportunities to better characterize neurologic features of PALF were not included in this study. Changes in clinical parameters over time may be useful to predict the outcome in liver failure (11). Continuous EEG patterns, which should include reactivity to painful or noxious stimuli (12), may help characterize dynamic features of HE in PALF and correlate them with clinical interventions. The assessment of biomarkers of inflammation, both intracerebral (13,14) and systemic (13,15), as well as brain injury (eg, S-100b, neuron-specific enolase) (16), may identify mechanistic and therapeutic targets. Monitoring optic nerve sheath diameter may be an adjunct or alternative method to assess increased ICP (17). A transcranial Doppler ultrasound to assess cerebral blood flow has been studied in children with sickle cell disease, traumatic brain injury, and stroke, but PALF was not mentioned in a review (18).
As a retrospective analysis of a clinical pathway, this study was not, and could not, be hypothesis based. Rather, experienced investigators at a single site incorporated their individual and collective clinical expertise and biases into a management plan that served as their local standard of care. Such is the nature of much of clinical investigation, and it is often a necessary initial step to develop an evidence-based clinical practice. This study generated numerable hypotheses that should be formally tested, but to do this requires time commitment by and financial support for investigators to generate and implement a protocol, families willing to consent for their children to participate in clinical research, collaborative investigators willing to test hypotheses for which there is clinical equipoise, infrastructure support for data collection and analysis, and sufficient funding to support these efforts. The alignment of these and other factors is necessary to move beyond this initial step toward better neurologic assessment in PALF.
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